The P’s and Q’s of cellular PrP-Aβ interactions

Prion disease research has opened up the “black-box” of neurodegeneration, defining a key role for protein misfolding wherein a predominantly alpha-helical precursor protein, PrP^C, is converted to a disease-associated, β-sheet enriched isoform called PrP^Sc. In Alzheimer disease (AD) the Aβ peptide derived from the β-amyloid precuror protein APP folds in β-sheet amyloid. Early thoughts along the lines of overlap may have been on target,¹ but were eclipsed by a simultaneous (but now anachronistic) controversy over the role of PrP^Sc in prion diseases.^2,3 Nonetheless, as prion diseases such as Creutzfeldt-Jakob Disease (CJD) are themselves rare and can include an overt infectious mode of transmission, and as familial prion diseases and familial AD involve different genes, an observer might reasonably have concluded that prion research could occasionally catalyze ideas in AD, but could never provide concrete overlaps at the mechanistic level. Surprisingly, albeit a decade or three down the road, several prion/AD commonalities can be found within the contemporary literature. One important prion/AD overlap concerns seeded spread of Aβ aggregates by intracerebral inoculation much like prions,⁴ and, with a neuron-to-neuron ‘spreading’ also reported for pathologic forms of other misfolded proteins, Tau^5,6 and α-synuclein in the case of Parkinson Disease.^7,8 The concept of seeded spread has been discussed extensively elsewhere, sometimes under the rubric of “prionoids”⁹, and lies outside the scope of this particular review where we will focus upon PrP^C. From this point the story can now be subdivided into four strands of investigation: (1) pathologic effects of Aβ can be mediated by binding to PrP^C,¹⁰ (2) the positioning of endoproteolytic processing events of APP by pathologic (β-cleavage + γ-cleavage) and non-pathologic (α-cleavage + γ-cleavage) secretase pathways is paralleled by seemingly analogous α- and β-like cleavage of PrP^C (Fig. 1) (3) similar lipid raft environments for PrP^C and APP processing machinery,^11-13 and perhaps in consequence, overlaps in repertoire of the PrP^C and APP protein interactors (“interactomes”),^14,15 and (4) rare kindreds with mixed AD and prion pathologies.¹⁶ Here we discuss confounds, consensus and conflict associated with parameters that apply to these experimental settings.     

The P’s and Q’s of cellular PrP-Aβ interactions

Prion disease research has opened up the “black-box” of neurodegeneration, defining a key role for protein misfolding wherein a predominantly alpha-helical precursor protein, PrP^C, is converted to a disease-associated, β-sheet enriched isoform called PrP^Sc. In Alzheimer disease (AD) the Aβ peptide derived from the β-amyloid precuror protein APP folds in β-sheet amyloid. Early thoughts along the lines of overlap may have been on target,¹ but were eclipsed by a simultaneous (but now anachronistic) controversy over the role of PrP^Sc in prion diseases.^2,3 Nonetheless, as prion diseases such as Creutzfeldt-Jakob Disease (CJD) are themselves rare and can include an overt infectious mode of transmission, and as familial prion diseases and familial AD involve different genes, an observer might reasonably have concluded that prion research could occasionally catalyze ideas in AD, but could never provide concrete overlaps at the mechanistic level. Surprisingly, albeit a decade or three down the road, several prion/AD commonalities can be found within the contemporary literature. One important prion/AD overlap concerns seeded spread of Aβ aggregates by intracerebral inoculation much like prions,⁴ and, with a neuron-to-neuron ‘spreading’ also reported for pathologic forms of other misfolded proteins, Tau^5,6 and α-synuclein in the case of Parkinson Disease.^7,8 The concept of seeded spread has been discussed extensively elsewhere, sometimes under the rubric of “prionoids”⁹, and lies outside the scope of this particular review where we will focus upon PrP^C. From this point the story can now be subdivided into four strands of investigation: (1) pathologic effects of Aβ can be mediated by binding to PrP^C,¹⁰ (2) the positioning of endoproteolytic processing events of APP by pathologic (β-cleavage + γ-cleavage) and non-pathologic (α-cleavage + γ-cleavage) secretase pathways is paralleled by seemingly analogous α- and β-like cleavage of PrP^C (Fig. 1) (3) similar lipid raft environments for PrP^C and APP processing machinery,^11-13 and perhaps in consequence, overlaps in repertoire of the PrP^C and APP protein interactors (“interactomes”),^14,15 and (4) rare kindreds with mixed AD and prion pathologies.¹⁶ Here we discuss confounds, consensus and conflict associated with parameters that apply to these experimental settings.     

The effects of stenting on coronary endothelium from a molecular biological view: Time for improvement?

Coronary artery stenting following balloon angioplasty represents the gold standard in revascularization of coronary artery stenoses. However, stent deployment as well as percutaneous transluminal coronary angioplasty (PTCA) alone causes severe injury of vascular endothelium. The damaged endothelium is intrinsically repaired by locally derived endothelial cells and by circulating endothelial progenitor cells from the blood, leading to re‐population of the denuded regions within several weeks to months. However, the process of re‐endothelialization is often incomplete or dysfunctional, promoting in‐stent thrombosis and restenosis. The molecular and biomechanical mechanisms that influence the process of re‐endothelialization in stented segments are incompletely understood. Once the endothelium is restored, endothelial function might still be impaired. Several strategies have been followed to improve endothelial function after coronary stenting. In this review, the effects of stenting on coronary endothelium are outlined and current and future strategies to improve endothelial function after stent deployment are discussed.     

Synthesis and biological study of new galanthamine-peptide derivatives designed for prevention and treatment of Alzheimer’s disease

Amino Acids - The Alzheimer’s disease leads to neurodegenerative processes and affecting negatively million people worldwide. The treatment of the disease is still difficult and incomplete in...     

The size of savannah Africa: a lion’s (Panthera leo) view

We define African savannahs as being those areas that receive between 300 and 1,500 mm of rain annually. This broad definition encompasses a variety of habitats. Thus defined, savannahs comprise 13.5 million km² and encompass most of the present range of the African lion (Panthera leo). Dense human populations and extensive conversion of land to human use preclude use by lions. Using high-resolution satellite imagery and human population density data we define lion areas, places that likely have resident lion populations. In 1960, 11.9 million km² of these savannahs had fewer than 25 people per km². The comparable area shrank to 9.7 million km² by 2000. Areas of savannah Africa with few people have shrunk considerably in the last 50 years and human population projections suggest they will likely shrink significantly in the next 40. The current extent of free-ranging lion populations is 3.4 million km² or about 25 % of savannah area. Habitats across this area are fragmented; all available data indicate that between 32,000 and 35,000 free-ranging lions live in 67 lion areas. Although these numbers are similar to previous estimates, they are geographically more comprehensive. There is abundant evidence of widespread declines and local extinctions. Under the criteria we outline, ten lion areas qualify as lion strongholds: four in East Africa and six in Southern Africa. Approximately 24,000 lions are in strongholds, with an additional 4,000 in potential ones. However, over 6,000 lions are in populations of doubtful long-term viability. Lion populations in West and Central Africa are acutely threatened with many recent, local extinctions even in nominally protected areas.     

Models and mechanisms of repeat expansion disorders: a worm’s eye view

The inappropriate genetic expansion of various repetitive DNA sequences underlies over 20 distinct inherited diseases. The genetic context of these repeats in exons, introns and untranslated regions has played a major role in thinking about the mechanisms by which various repeat expansions might cause disease. Repeat expansions in exons are thought to give rise to expanded toxic protein repeats (i.e. polyQ). Repeat expansions in introns and UTRs (i.e. FXTAS) are thought to produce aberrant repeat-bearing RNAs that interact with and sequester a wide variety of essential proteins, resulting in cellular toxicity. However, a new phenomenon termed ‘repeat-associated nonAUG dependent (RAN) translation’ paints a new and unifying picture of how distinct repeat expansion-bearing RNAs might act as substrates for this noncanonical form of translation, leading to the production of a wide range of repeat sequence-specific-encoded toxic proteins. Here, we review how the model system Caenorhabditis elegans has been utilized to model many repeat disorders and discuss how RAN translation could be a previously unappreciated contributor to the toxicity associated with these different models.     

An ant’s eye view of culture: propagation of new traditions through triggering dormant behavioural patterns

We consider a previously unknown way of propagation of behavioural traditions in animal communities using hunting in ants as an example. We experimentally revealed that common litter dwelling ants Myrmica rubra effectively hunt jumping prey and the way the hunting behavioural pattern is distributed within ant colonies is rather sophisticated. Comparison of our results with those obtained on vertebrates enables us to suggest that “distributed social learning” plays an important role in spreading new traditions in animal communities: initial performances by a few carriers of an “at once and entirely” available behavioural pattern propagate this pattern among specimens which have only dormant “sketches” of it. Spread of these behaviours in populations is based on relatively simple forms of social learning such as social facilitation which underlies species’ predisposition to learn certain sequences of behavioural acts. To be triggered, carriers of dormant “sketches” of a relevant behavioural pattern should encounter performances of this pattern with sufficient frequency. We call this strategy triggering of dormant behavioural patterns. Integration of behaviour thus takes place not only at the individual level but at the population level as well.     

Pandora’s box down-under: origins and numbers of mustelids transported to New Zealand for biological control of rabbits

This paper describes one of the world’s first large-scale experiments in biological control of a major vertebrate pest of agriculture, which was tried in New Zealand during the second half of the nineteenth century. Starting from the late 1860s, pasture damage in Southland and Otago by European rabbits was causing serious reductions in productivity of sheep (wool clip and lambing percentages) associated with malnutrition of the breeding ewes, and a consequent decline in the value of pastoral land. In response, and despite repeated local and international warnings, ferrets, stoats and weasels (Mustela furo, M. erminea and M. nivalis) were liberated on the worst of the rabbit-infested pastures. They were perceived as the ‘natural enemies of the rabbit’ but (unlike foxes) too small to threaten lambs. Over the 50 years after 1870, upwards of 75,000 ferrets, most imported from Australia or locally bred, were released in the South Island. Over the decade 1883–1892, at least 7838 stoats and weasels arrived from Britain. At least 25 shipments are known, with an average of only 10% mortality per shipment. Of the 3585 animals listed by species, 73% were weasels. The total cost of the ferret programme cannot now be estimated; that of stoats and weasels alone was at least £5441, probably twice that, or >$NZ 1–2 million in today’s money. Mustelids (and cats) killed many young rabbits, which was helpful because rates of change in rabbit populations are sensitive to variations in juvenile mortality, but in the most rabbit-prone semi-arid lands, mustelids could not remove enough rabbits to prevent the continuing damage to sheep pastures. The era of deliberate introductions of mustelids to control rabbits in New Zealand was short, expensive, and unsuccessful.     

The ribosome’s energy landscape: Recent insights from computation

Biophysical Reviews - The ever-increasing capacity of computing resources has extended ribosome calculations from the study of small-scale fluctuations to large-scale barrier-crossing processes. As...     

The Patient’s View: Issues of Theory and Practice

Almost all the knowledge now produced about psychiatry includes what is called “the patient’s or client’s perspective.” This paper analyzes how this notion has been framed in the discourses on mental health over the last two decades, particularly in mental health research and in anthropology. The very concept of the “patient’s perspective” is a social and historical construct. Despite its remarkable prevalence, the notion remains vague. Mental health research pictures it as a stable attribute of the individual. Anthropologists integrate the contextual nature of the patient view; but they still largely envision the psychiatric patient as a rational actor producing narratives based on common sense. However, in psychiatric practice, the client’s perspective is not something the patient individually produces; it is rather shaped by and in a context. To explore this process, my research investigated interactions between staff and patients in a French community mental health center, and showed that the client’s perspective is the result of a collective process. Further analysis demonstrates that eliciting or producing the patient’s view is sometimes considered a therapeutic goal in itself, since being granted the status of a rational and narrative actor gives access to the most valued model of care, one that is based on partnership. Being an outcome that is negotiated between patients and care providers, the “patient’s view” then becomes a new resource in mental health settings.

The ‘39 steps’: an algorithm for performing statistical analysis of data on energy intake and expenditure

The epidemics of obesity and diabetes have aroused great interest in the analysis of energy balance, with the use of organisms ranging from nematode worms to humans. Although generating energy-intake or -expenditure data is relatively straightforward, the most appropriate way to analyse the data has been an issue of contention for many decades. In the last few years, a consensus has been reached regarding the best methods for analysing such data. To facilitate using these best-practice methods, we present here an algorithm that provides a step-by-step guide for analysing energy-intake or -expenditure data. The algorithm can be used to analyse data from either humans or experimental animals, such as small mammals or invertebrates. It can be used in combination with any commercial statistics package; however, to assist with analysis, we have included detailed instructions for performing each step for three popular statistics packages (SPSS, MINITAB and R). We also provide interpretations of the results obtained at each step. We hope that this algorithm will assist in the statistically appropriate analysis of such data, a field in which there has been much confusion and some controversy.     

Oxazine dye-conjugated dna oligonucleotides: Förster resonance energy transfer in view of molecular dye-DNA interactions

In this work, the photophysical properties of two oxazine dyes (ATTO 610 and ATTO 680) covalently attached via a C6-amino linker to the 5'-end of short single-stranded as well as double-stranded DNA (ssDNA and dsDNA, respectively) of different lengths were investigated. The two oxazine dyes were chosen because of the excellent spectral overlap, the high extinction coefficients, and the high fluorescence quantum yield of ATTO 610, making them an attractive F?rster resonance energy transfer (FRET) pair for bioanalytical applications in the far-red spectral range. To identify possible molecular dye-DNA interactions that cause photophysical alterations, we performed a detailed spectroscopic study, including time-resolved fluorescence anisotropy and fluorescence correlation spectroscopy measurements. As an effect of the DNA conjugation, the absorption and fluorescence maxima of both dyes were bathochromically shifted and the fluorescence decay times were increased. Moreover, the absorption of conjugated ATTO 610 was spectrally broadened, and a dual fluorescence emission was observed. Steric interactions with ssDNA as well as dsDNA were found for both dyes. The dye-DNA interactions were strengthened from ssDNA to dsDNA conjugates, pointing toward interactions with specific dsDNA domains (such as the top of the double helix). Although these interactions partially blocked the dye-linker rotation, a free (unhindered) rotational mobility of at least one dye facilitated the appropriate alignment of the transition dipole moments in doubly labeled ATTO 610/ATTO 680-dsDNA conjugates for the performance of successful FRET. Considering the high linker flexibility for the determination of the donor-acceptor distances, good accordance between theoretical and experimental FRET parameters was obtained. The considerably large F?rster distance of ~7 nm recommends the application of this FRET pair not only for the detection of binding reactions between nucleic acids in living cells but also for monitoring interactions of larger biomolecules such as proteins.     

Controls for Immunohistochemistry: The Histochemical Society’s Standards of Practice for Validation of Immunohistochemical Assays

Immunohistochemistry is widely used in biomedical research to localize specific epitopes of molecules in cells and tissues. The validity of interpretations based on immunohistochemistry requires appropriate positive and negative controls that are often not reported in publications. This omission may lead to incorrect interpretations and irreproducible results in the literature and contribute to wasted time, effort, and resources as well as erosion of confidence in scientific investigation by the general public, legislative bodies and funding agencies. The present article summarizes essential controls required for validation of immunohistochemical findings and represents a standard of practice for the use of immunohistochemistry in research and diagnostic investigations. Adherence to the guidelines described in the present article can be cited by authors as support for the validity of interpretations of the immunohistochemistry reported in their publications.     

The discovery of slowness: Time to deconstruct Gretzky’s and Messi’s predictive brains

Jafari and Smith hypothesized that time during games may pass slower for the world’s best football player, Lionel Messi, from Argentina. This hypothesis leads to two questions: How can we explain such temporal paradox and how could this explain his dominant performances? Remarkably, the Argentinian’s case was preceded by the equally astonishing case of Wayne Gretzky: The Canadian considered ice hockey as a rather slow game and was the best player in the sport’s history. Whether Messi’s and Gretzky’s motor neurons fire faster, (inter)act differently or whether other mechanisms are at (inter)play warrants targeted research. A further explanation for such dominance of football and ice hockey, respectively, could be that both athletes “buy time”: To this end, automized motor skills may allow their predictive brains to make better use of time than other players to read the games and plan ahead. Deconstructing predictive minds of outperforming individuals like Gretzky and Messi could provide unique options to elucidate how differential time perception may make performances in athletes, and beyond, more swift and more efficient.     

Natural photosystems from an engineer’s perspective: length,time, and energy scales of charge and energy transfer

The vast structural and functional information database of photosynthetic enzymes includes, in addition to detailed kinetic records from decades of research on physical processes and chemical reaction-pathways, a variety of high and medium resolution crystal structures of key photosynthetic enzymes. Here, it is examined from an engineer’s point of view with the long-term goal of reproducing the key features of natural photosystems in novel biological and non-biological solar-energy conversion systems. This survey reveals that the basic physics of the transfer processes, namely, the time constraints imposed by the rates of incoming photon flux and the various decay processes allow for a large degree of tolerance in the engineering parameters. Furthermore, the requirements to guarantee energy and electron transfer rates that yield high efficiency in natural photosystems are largely met by control of distance between chromophores and redox cofactors. This underlines a critical challenge for projected de novo designed constructions, that is, the control of spatial organization of cofactor molecules within dense array of different cofactors, some well within 1 nm from each other.